Enhancing Corticospinal Regeneration after SCI
Funded in: 2017, 2018, 2019
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Problem: Reduced regeneration of adult axon in the CNS
Target: The intrinsic growth capacity of adult neurons
Goal: To enhance regeneration of injured CNS axons and improve function.
During development, neurons extend axons throughout the nervous system, establishing connections with targets that are often long distances away. The ability of these young neurons to robustly extend their axons is dramatically diminished in adulthood, and this reduced intrinsic growth capacity is a key mechanism underlying the inability of adult central nervous system (CNS) neurons to regenerate their axons following injury. Because of the failure of CNS axons to spontaneously regenerate, functional impairments are often permanent. Hence, there remains a great unmet need for therapeutic strategies to enhance regeneration of injured CNS axons and thereby improve function.
Recently our group has shown that neural stem cells transplanted into an injured spinal cord provide a platform into which CNS motor axons readily regenerate (Kadoya, et al., 2016). This remarkable progress shows that neurons retain their ability to regenerate during adulthood. However, the mechanisms by which this is accomplished are poorly understood.
Here we aim to identify how an adult motor neuron initiates regrowth of injured nerve fibers and finds the correct target for re-innervation. We will first identify which genes are active in regenerating motor neurons. A cloud-based computer infrastructure will help link this genetic code to pharmacological drugs through the Broad Connectivity Database. Chemical libraries of over 3,000 drugs currently on the market or in clinical trials will be compared to our motor neuron genetic code to identify previously unrecognized connections between drugs and their targets. This comparison will bring to light new drugs to enhance axon regeneration. Predicted pharmaceutical agents will be tested in animal models of spinal cord injury to determine their therapeutic value. If successful, this work could develop novel strategies to improve function after spinal cord injury and take a rapid path towards human intervention, as some of these drugs are already FDA approved.